Broad-spectrum mono- and combinational drug therapies for global viral pandemic preparedness

Broadly effective antiviral therapies must be developed to be ready for clinical trials, which should begin soon after the emergence of new life-threatening viruses. Here, we pave the way towards this goal by analyzing conserved druggable virus-host interactions, mechanisms of action and immunomodulatory properties of broad-spectrum antivirals (BSAs), routes of BSA delivery, and BSA interactions with other antivirals. Based on the analysis we developed scoring systems, which allowed us to predict novel BSAs and BSA-containing drug combinations (BCCs). Thus, we have developed a new strategy to broaden the spectrum of BSA indications and predict novel mono- and combinational therapies that can help better prepare for imminent future viral outbreaks.

Host related factors determine co-occurrence patterns between pathogenic bacteria, protozoa, and helminths in populations of the multimammate mouse, Mastomys natalensis

Advances in experimental and theoretical work increasingly suggest that parasite interactions within a single host can affect the spread and severity of wildlife diseases. Yet empirical data to support predicted co-infection patterns are limited due to the practical challenges of gathering convincing data from animal populations and the stochastic nature of parasite transmission. Here, we investigated co-infection patterns between micro- (bacteria and protozoa) and macroparasites (gastrointestinal helminths) in natural populations of the multimammate mouse (Mastomys natalensis). Fieldwork was performed in Morogoro (Tanzania), where we trapped 211 individual M. natalensis and tested their behavior using a modified open-field arena. All animals were checked on the presence of helminths in their gastrointestinal tract, three bacteria (Anaplasma, Bartonella, and Borrelia) and two protozoan genera (Piroplasma and Hepatozoon). Besides the presence of eight different helminth genera (reported earlier), we found that 21% of M. natalensis were positive for Anaplasma, 13% for Bartonella, and 2% for Hepatozoon species. Hierarchical modelling of species communities was used to investigate the effect of the different host-related factors on these parasites infection probability and community structure. Our results show that the infection probability of Anaplasma and Bartonella was higher in adults than juveniles. We also observed that females and less explorative individuals had a higher infection probability with Bartonella. We found limited support for within-host interactions between micro-and macroparasites, as only animals infected with Bartonella were significantly more likely to be infected with Protospirura, Trichuris, and Trichostrongylidae helminths.

Schistosoma mansoni α-N-acetylgalactosaminidase (SmNAGAL) regulates coordinated parasite movement and egg production

α-galactosidase (α-GAL) and α-N-acetylgalactosaminidase (α-NAGAL) are two glycosyl hydrolases responsible for maintaining cellular homeostasis by regulating glycan substrates on proteins and lipids. Mutations in the human genes encoding either enzyme lead to neurological and neuromuscular impairments seen in both Fabry- and Schindler/Kanzaki- diseases. Here, we investigate whether the parasitic blood fluke Schistosoma mansoni, responsible for the neglected tropical disease schistosomiasis, also contains functionally important α-GAL and α-NAGAL proteins. As infection, parasite maturation and host interactions are all governed by carefully-regulated glycosylation processes, inhibiting S. mansoni’s α-GAL and α-NAGAL activities could lead to the development of novel chemotherapeutics. Sequence and phylogenetic analyses of putative α-GAL/α-NAGAL protein types showed Smp_089290 to be the only S. mansoni protein to contain the functional amino acid residues necessary for α-GAL/α-NAGAL substrate cleavage. Both α-GAL and α-NAGAL enzymatic activities were higher in females compared to males (p<0.05; α-NAGAL > α-GAL), which was consistent with smp_089290’s female biased expression. Spatial localisation of smp_089290 revealed accumulation in parenchymal cells, neuronal cells, and the vitellaria and mature vitellocytes of the adult schistosome. siRNA-mediated knockdown (>90%) of smp_089290 in adult worms significantly inhibited α-NAGAL activity when compared to control worms (siLuc treated males, p<0.01; siLuc treated females, p<0.05). No significant reductions in α-GAL activities were observed in the same extracts. Despite this, decreases in α-NAGAL activities correlated with a significant inhibition in adult worm motility as well as in egg production. Programmed CRISPR/Cas9 editing of smp_089290 in adult worms confirmed the egg reduction phenotype. Based on these results, Smp_089290 was determined to act predominantly as an α-NAGAL (hereafter termed SmNAGAL) in schistosome parasites where it participates in coordinating movement and oviposition processes. Further characterisation of SmNAGAL and other functionally important glycosyl hydrolases may lead to the development of a novel anthelmintic class of compounds.

Protein Tyrosine and Serine/Threonine Phosphorylation in Oral Bacterial Dysbiosis and Bacteria-Host Interaction

The human oral cavity harbors approximately 1,000 microbial species, and dysbiosis of the microflora and imbalanced microbiota-host interactions drive many oral diseases, such as dental caries and periodontal disease. Oral microbiota homeostasis is critical for systemic health. Over the last two decades, bacterial protein phosphorylation systems have been extensively studied, providing mounting evidence of the pivotal role of tyrosine and serine/threonine phosphorylation in oral bacterial dysbiosis and bacteria-host interactions. Ongoing investigations aim to discover novel kinases and phosphatases and to understand the mechanism by which these phosphorylation events regulate the pathogenicity of oral bacteria. Here, we summarize the structures of bacterial tyrosine and serine/threonine kinases and phosphatases and discuss the roles of tyrosine and serine/threonine phosphorylation systems in Porphyromonas gingivalis and Streptococcus mutans, emphasizing their involvement in bacterial metabolism and virulence, community development, and bacteria-host interactions.

Gain-of-function genetic screening identifies the antiviral function of TMEM120A via STING activation

Zika virus (ZIKV) infection can be associated with neurological pathologies, such as microcephaly in newborns and Guillain-Barre syndrome in adults. Effective therapeutics are currently not available. As such, a comprehensive understanding of virus-host interactions may guide the development of medications for ZIKV. Here we report a human genome-wide overexpression screen to identify host factors that regulate ZIKV infection and find TMEM120A as a ZIKV restriction factor. TMEM120A overexpression significantly inhibits ZIKV replication, while TMEM120A knockdown increases ZIKV infection in cell lines. Moreover, Tmem120a knockout in mice facilitates ZIKV infection in primary mouse embryonic fibroblasts (MEF) cells. Mechanistically, the antiviral activity of TMEM120A is dependent on STING, as TMEM120A interacts with STING, promotes the translocation of STING from the endoplasmic reticulum (ER) to ER-Golgi intermediate compartment (ERGIC) and enhances the phosphorylation of downstream TBK1 and IRF3, resulting in the expression of multiple antiviral cytokines and interferon-stimulated genes. In summary, our gain-of-function screening identifies TMEM120A as a key activator of the antiviral signaling of STING.

Metabolic Processes Are Differentially Regulated During Wild-Type and Attenuated Dengue Virus Infection in Aedes aegypti

Successful completion of the dengue virus (DENV) life cycle in its mosquito vectors is important for efficient human–mosquito–human cycle of transmission, but the virus–mosquito interactions that underpin this critical event are poorly defined. To understand the virus–host interactions that determine viral infection by Aedes aegypti, the principal DENV vector, the authors compared transcriptomic changes in the head/thorax of the mosquito after intrathoracic infection with the wild-type DENV2 16681 strain and its attenuated derivative, PDK53. Using high-throughput RNA-sequencing, the authors identified 1,629 differentially expressed genes (DEGs) during 16681 infection, compared with only 22 DEGs identified during PDK53 infection, indicating that 16681 infection triggers a more robust host transcriptomic response compared with PDK53 infection. The authors further found that 16681 infection, but not PDK53 infection, altered metabolism in these heads/thoraces. Altogether, our findings reveal differential regulation of metabolic processes during wild-type and attenuated DENV infection, and suggest the need for future work to study the role of metabolic processes in determining DENV infection and replication in its mosquito vectors.

The Clash of Microbiomes: From the Food Matrix to the Host Gut

Food fermentation has led to the improvement of the safety characteristics of raw materials and the production of new foodstuffs with elevated organoleptic characteristics. The empirical observation that these products could have a potential health benefit has garnered the attention of the scientific community. Therefore, several studies have been conducted in animal and human hosts to decipher which of these products may have a beneficial outcome against specific ailments. However, despite the accumulating literature, a relatively small number of products have been authorized as ‘functional foods’ by regulatory bodies. Data inconsistency and lack of in-depth preclinical characterization of functional products could heavily contribute to this issue. Today, the increased availability of omics platforms and bioinformatic algorithms for comprehensive data analysis can aid in the systematic characterization of microbe–microbe, microbe–matrix, and microbe–host interactions, providing useful insights about the maximization of their beneficial effects. The incorporation of these platforms in food science remains a challenge; however, coordinated efforts and interdisciplinary collaboration could push the field toward the dawn of a new era.

LRRC15 suppresses SARS-CoV-2 infection and controls collagen production

Although ACE2 is the primary receptor for SARS-CoV-2 infection, a systematic assessment of factors controlling SARS-CoV-2 host interactions has not been described. Here we used whole genome CRISPR activation to identify host factors controlling SARS-CoV-2 Spike binding. The top hit was a Toll-like receptor-related cell surface receptor called leucine-rich repeat-containing protein 15 (LRRC15). LRRC15 expression was sufficient to promote SARS-CoV-2 Spike binding where it forms a cell surface complex with LRRC15 but does not support infection. Instead, LRRC15 functioned as a negative receptor suppressing both pseudotyped and live SARS-CoV-2 infection. LRRC15 is expressed in collagen-producing lung myofibroblasts where it can sequester virus and reduce infection in trans. Mechanistically LRRC15 is regulated by TGF-β, where moderate LRRC15 expression drives collagen production but high levels suppress it, revealing a novel lung fibrosis feedback circuit. Overall, LRRC15 is a master regulator of SARS-CoV-2, suppressing infection and controlling collagen production associated with “long-haul” COVID-19.